DESCRIPTION: Most epidemiologic studies of risk factors for Alzheimer's diseas are limited to clinically diagnosed disease. The proposed study offers the opportunity to integrate pathologic clinical data, and thereby examine the mechanisms through which risk factors for Alzheimer's disease lead to clinical expression of the disease. Preliminary data for two risk factors, the apolipoprotein E Epsilon 4 allele and years of formal education, suggest that they lead to a clinical disease through dissimilar mechanisms. Although both are associated with clinical disease the epsilon 4 allele is related to recognized Alzheimer's disease pathology, but years of formal education is not We will test the hypotheses that the apolipoprotein E epsilon 4 allele alters risk of clinical disease through its association with amyloid deposition and neurofibrillary changes, that years of formal education and female gender alte risk of clinical disease through their association with neuronal counts and synaptic density and that subcortical brain infarctions alter risk of clinical disease by increasing the likelihood that Alzheimer's disease pathology is clinically expressed. The study will also characterize the relation of age to pathologic and clinical expression of disease and describe how age modifies th relation of post-mortem indices to the clinical expression of Alzheimer's disease. The findings from the proposed study may have profound implications for therapeutic intervention and disease prevention. Hypothesis testing requires risk factor information, longitudinal structured quantitative clinica data collected proximate to death and brain tissue. The proposed project will collect new post-mortem data and link it to available risk factor information and clinical data in innovative analyses. The Religious Orders Study (ROS) which performs annual clinical evaluations on more than 650 nuns, priests, and brothers over the age of 65 who have agreed to brain donation after death, provides and ideal source of longitudinal clinical data and of brain tissue fo the proposed project.